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Viral Diseases - HANTAVIRUS PULMONARY SYNDROME

INTRODUCTION:

On May 14, 1993, the New Mexico Department of Health was notified of 2 persons who had died within 5 days of each other. Their illnesses were characterized by abrupt onset of fever, myalgia, headache, and cough, followed by the rapid development of respiratory failure. Tests for Yersinia pestis and other bacterial and viral pathogens were negative. After additional persons who had recently died following a similar clinical course were reported by the Indian Health Service, the health services of Arizona, Colorado and Utah were contacted to seek other possible cases. Blood and tissue specimens were sent to the Centers for Disease Control and Prevention (CDC). The results were negative except for signals for the Puumala hantavirus. Relying on molecular and immunological research performed by the Army, the National Institutes of Health, and the CDC itself, by June 9th, the CDC was able to prove that a new hantavirus was the culprit (1). As of November 5th, laboratory evidence of acute hantavirus infection had been confirmed in 42 persons. Twenty-six (62%) of these persons have died. Most cases were in the Southwest but some have been reported as far afield as North Dakota and California (1). This paper presents a brief overview of hantavirus infections with primary focus on Hantavirus Pulmonary Syndrome (HPS) and recommended laboratory precautions to reduce the risk of accidental exposure. Other detailed reviews are available elsewhere (2-7). 

AGENT:

Isolation of the first recognized hantavirus (Hantaan virus) was reported from the Republic of Korea in 1978. The genus Hantavirus is a member of the family Bunyaviridae. Hantaviruses are further divided into genotypes. Representative viruses in each genotype are the Hantaan virus, the Seoul virus, the Puumala virus, and the Prospect Hill virus. Additional groups exist. Hantaan, Puumala, and Seoul viruses are known human pathogens; Prospect Hill has not been associated with disease. The causative agent of HPS represents a previously unidentified genotype. Since the 1930s, epidemic and sporadic hantavirus-associated disease has been described throughout Eurasia, especially in Scandinavia and Northeastern Asia. In the 1950s, thousands of United Nations military personnel were infected with hantavirus during the Korean conflict; more recently, transmission has been documented among United States military personnel training in the Republic of Korea. Hantaviruses have been isolated from rodents in the United States, and serological studies have documented human infections with hantaviruses. However, acute disease associated with infection by pathogenic hantaviruses has not previously been reported in the Western Hemisphere (8). Previously called the Four Corners Virus and Muerto Canyon Virus, the causative genotype for HPS is now called Sin Nombre Virus. 

DISEASE IN HUMANS:

The clinical manifestations previously associated with hantavirus infections have been characterized by hemorrhagic features and by renal involvement. In HPS, however, onset of illness has been characterized by a prodrome consisting of fever, myalgia, and variable respiratory symptoms followed by the abrupt onset of acute respiratory distress. Other symptoms reported during the early phase of illness have included headache and gastrointestinal complaints. Hemoconcentration and thrombocytopenia have developed in a majority of the cases. The hospital course has been characterized by bilateral pulmonary infiltration, fever, hypoxia, and hypotension; recovery in survivors has been without sequelae. It is important to note that no defined set of symptoms and signs reliably distinguishes HPS from other forms of noncardiogenic pulmonary edema or adult respiratory distress syndrome (9). Postmortem examination has routinely revealed serous pleural effusions and heavy edematous lungs. Microscopic findings have included interstitial infiltrates of mononuclear cells in the alveolar septa, congestion, septal and alveolar edema with or without mononuclear cell exudate, focal hyaline membranes, and occasional alveolar hemorrhage. Large mononuclear cells with the appearance of immunoblasts have been found in red and periarteriolar white pulp of the spleen, hepatic portal triads, and other sites. Hantavirus antigens, localized primarily in endothelial cells, have been detected in most organs, with marked accumulations in the lungs (9). The incubation period for the known pathogenic hantaviruses, although highly variable, generally range from 2 to 4 weeks (8). Based on reported cases, the incubation period for HPS appears to be one to three weeks (10). 

RESERVOIRS:

Rodents are the primary reservoir hosts with each hantavirus appearing to have a preferential rodent host. The epidemiological characteristics of outbreaks of human disease and the severity for the infection are determined mainly by the rodent host. Available data strongly supports the deer mouse (Peromyscus maniculatus) as the primary reservoir of the newly recognized hantavirus (11). Serologic evidence of infection has also been found in pi¤on mice (P. truei) and the brush mice (P. boylii). Other rodent species that have tested positive so far include the house mouse (Mus musculus), the harvest mouse (Reithrodontomys sp.), the rock squirrel (Spermophalus variegatus), the white-throated wood rat (Neotoma albigula), and the western chipmunk (Tamias spp.). P. maniculatus is highly adaptable and is found in different habitats, including human residences in rural and semirural areas, but generally not in urban centers (12). The wood mouse or striped field mouse (Apodemus sp.) associated hantaviruses also cause severe human disease with mortality rates between 3 and 7%. Rattus associated disease is less severe and asymptomatic infections may be more common. The most benign form of hantaviral disease (HVD), also called Nephropathia epidemica and first described in Scandinavia, is caused by a hantavirus that infects voles (Clethrionomys species). Infected voles and human disease occur throughout western Europe (13). The hantaviruses have been identified in other animals. At the International Symposium on Hemorrhagic Fever with Renal Syndrome (HFRS), Leningrad, 5-10 May 1991, the presence of hantaviral antigen was reported in 13 species of birds in eastern parts of the former U.S.S.R. (13). The CDC is also investigating whether other animals, particularly those that prey on rodents, may carry the virus. The impetus for this research is a 1987 study suggesting that cats, which tested positive for two other hantaviruses-the Hantaan and Seoul types-may help transmit the virus to humans in China. As for the HPS virus, so far CDC scientists have identified one infected nonrodent species (aside from humans): the desert cottontail (Sylvilagus auduboni). But virologists think most nonrodents are "dead-end" hosts that shed little virus and are unlikely to infect people (14). Laboratory rats, which were a reservoir of hantavirus, have been responsible for several outbreaks of HVD among animal caretakers and laboratory workers at research institutions in Korea, China, the former Soviet Union, Japan, Scandinavia, the U.K., France, the Netherlands and Belgium (13). Transmission of Hantavirus from laboratory reared mice and rats has not been documented in the United States. 

TRANSMISSION:

Susceptibility of rodents may vary depending on the combination of rodent species and virus strains; however, Hantaviruses do not cause apparent illness in their reservoir hosts (15). In rodents, the virus is detected primarily in the lung and kidney, where it persists despite the presence of serum antibodies. Infected rodents shed large quantities of virus in saliva, urine, and feces for many weeks, but the duration and period of maximum infectivity are unknown. Although the main route of transmission is aerosolization, the demonstrated presence of infectious virus in saliva of infected rodents and the marked sensitivity of these animals to hantaviruses following inoculation suggests that biting may also be an important mode of transmission among rodents (12). Arthropod vectors are not known to have a role in the transmission of hantaviruses. Domestic animals may bring infected rodents into contact with humans (12). Human infection may occur when infective saliva or excreta are inhaled as aerosols produced directly from the animal. Transmission may also occur when dried materials contaminated by rodent excreta are disturbed, directly introduced into broken skin, introduced onto the conjunctivae, or, possibly, ingested in contaminated food or water. Persons have also become infected after being bitten by rodents (12). Person-to-person transmission has not been associated with any of the previously identified hantaviruses nor with the recent outbreak in the Southwest (16). In the current epidemic, known hantavirus infections of humans have occurred primarily in adults and are associated with domestic, occupational, or leisure activities that bring humans into contact with infected rodents, usually in a rural setting. Cases have been epidemiologically associated with the following situations: Planting or harvesting field crops Occupying previously vacant cabins or other dwellings Cleaning barns and other outbuildings Disturbing rodent-infested areas while hiking or camping Inhabiting dwellings with indoor rodent populations Residing in or visiting areas in which the rodent population has shown an increase in density (12). In Europe, isolation of hantaviruses from immunocytomas and ascites tumors has highlighted additional risks from working with persistently infected rodents. Tumors, passaged over the years in hantavirus-infected laboratory rats, transfer the virus when implanted in hantavirus-free rats. Since, in rodents, hantaviruses are not transmitted vertically but horizontally, the use of caesarian section and foster mother techniques have been recommended for laboratories breeding rodent colonies. Before implantation, tumors should be checked for the presence of the hantaviruses (this precaution should be followed by laboratory workers in the U.S. importing tumors, organs, or live rodents from hantavirus endemic areas) (12). 

DIAGNOSIS:

The CDC in consultation with the Council of State and Territorial Epidemiologists has developed screening criteria for HPS (9). Cases meeting the screening criteria should be reported to the CDC through state health departments. These criteria are: Potential case-patients must have one of the following: a febrile illness (temperature ò101 oF [ò38.3 oC]) occurring in a previously healthy person characterized by unexplained adult respiratory distress syndrome, or bilateral interstitial pulmonary infiltrates developing within 1 week of hospitalization with respiratory compromise requiring supplemental oxygen, OR an unexplained respiratory illness resulting in death in conjunction with an autopsy examination demonstrating noncardiogenic pulmonary edema without an identifiable specific cause of death. Potential case-patients are to be excluded if they have any of the following: a predisposing underlying medical condition (e.g., severe underlying pulmonary disease, solid tumors or hematologic malignancies, congenital or acquired immunodeficiency disorders, or medical conditions [e.g., rheumatoid arthritis or organ transplant recipients] requiring immunosuppressive drug therapy [e.g., steroids or cytotoxic chemotherapy]). an acute illness that provides a likely explanation for the respiratory illness (e.g., recent major trauma, burn, or surgery; recent seizures or history of aspiration; bacterial sepsis; another respiratory disorder such as respiratory syncytial virus in young children; influenza; or legionella pneumonia). Confirmed case-patients must have the following: at least one specimen (i.e., serum and/or tissue) available for laboratory testing for evidence of hantavirus infection. AND in a patient with a compatible clinical illness, diagnosis is confirmed when any of the following criteria are met: IgM antibodies to hantavirus antigens, fourfold or greater increase in immunoglobulin G titers to hantavirus antigens in paired serum specimens, a positive immunohistochemical stain for hantavirus antigen in tissues, or positive polymerase chain reaction (PCR) for hantavirus ribonucleic acid. Currently, diagnosis of the HPS strain of Hantavirus in animals is in its infancy. IFA based tests offered by national research laboratories may be used for screening; however, false negatives can occur depending on the antigen used. PCR remains the method of choice for strain identification. Presently, one laboratory (Rockefeller University Laboratory Animal Research Center, [212]327-8522) offers this service with more, hopefully, coming on line in the future (17). 

TREATMENT:

Supportive care and meticulous monitoring of vital signs and fluid balance are the basis for therapy. Severe hypoxia and overhydration should be avoided or prevented. Pressors or cardiotonic drugs should be employed to maintain perfusion without excessive fluid administration (9). In one controlled study involving HFRS, intravenous administration of the antiviral drug ribavirin was effective in treating severe cases of hantavirus infection when administered early in the course of illness (8). The effectiveness of using ribavirin to treat HPS has not been established, yet. 

PREVENTION AND CONTROL:

Hantaviruses have lipid envelopes that are susceptible to most disinfectants (e.g., dilute hypochlorite solutions, detergents, ethyl alcohol (70%), or most general-purpose household disinfectants). How long these viruses survive after being shed in the environment is uncertain (12). The reservoir hosts of the hantavirus in the southwestern United States also act as hosts for the bacterium Yersinia pestis, the etiology agent of plague. Although fleas and other ectoparasites are not known to play a role in hantavirus epidemiology, rodent fleas transmit plague. Control of rodents without concurrent control of fleas may increase the risk of human plague as the rodent fleas seek an alternative food source. Thus, eradicating the reservoir hosts of hantaviruses is neither feasible nor desirable. Once the virus has been cultured, it might be possible to develop a vaccine against the HPS strain. However, currently, the best available approach for disease control and prevention is risk reduction through environmental hygiene practices that deter rodents from colonizing the home and work environment (12). No restriction of travel to areas affected by this outbreak is considered necessary; however, activities that may disrupt rodent burrows or result in contact with rodents or aerosolization or rodent excreta should be avoided. Laboratory workers practicing universal precautions while processing routine clinical materials (such as blood, urine, and respiratory specimens) are not considered to be at increased risk for hantavirus infection. However, laboratory-acquired infections have occurred among persons who handled infected wild or laboratory rodents. Therefore, laboratory work that may result in propagation of hantaviruses should be conducted in a special facility (biosafety level 3) (8). Recommendations for laboratory animal facilities housing wild-caught rodents include: Access to rooms should be restricted to only those individuals who have a legitimate need to be in the room. Colony should be serologically screened for the agent. Animals should be housed and handled under standard microisolation techniques. Biological safety cabinets should be used and not laminar flow workbenches. Until the status of the colony can be ascertained, individuals working with the rodent should: a. Obtain a baseline serum sample. The serum should be stored at -20oC. b. Insure that all persons involved are informed of the symptoms of the disease and given detailed guidance on prevention measures. c. Seek immediate medical attention if a febrile or respiratory illness develops within 45 days of the last potential exposure. The attending physician should be informed of the potential occupational risk of hantavirus infection. d. Wear an half-face air-purifying (or negative-pressure) respirator or powered air-purifying respirator with HEPA filter when handling rodents or their cages. Respirators are not considered protective if facial hair interferes with the face seal. Respirators should be fitted by trained personnel in accordance with OSHA standards. e. Wear rubber or plastic gloves when handling rodents or cages. Gloves should be washed and disinfected before removing them. f. Wear dedicated outer garments (disposable, if possible), rubber boots or disposable shoe covers and protective goggles. Personal protective gear should be decontaminated upon removal. If not disposable, they should be laundered on site using hot water and detergent. Machine-dry using a high setting. If no laundry facilities are available, non-disposable items should be immersed in liquid disinfectant until they can be washed. All potentially infective waste material (including respirator filters, bedding, caging, disposable protective garments, and used disposables such as syringes, gauze, etc.) should be placed in autoclavable plastic bags and sterilized. Needles, scalpels, pipettes, and other sharp materials should be placed in puncture proof containers and sterilized. Spread from feral rodents was postulated as the cause of one source of contamination (18). Therefore, facilities and individual rooms should be vermin-proof to prevent accidental egress and ingress of rodents. All openings greater than ¬ inch should be screened or sealed. Carcasses should be placed in a plastic bag and disposed as biohazard waste or incinerated. Since feral rodents may transmit the disease, it is recommended that Hantavirus testing be included in animal health monitoring programs. Why the Current Epidemic? Because of the rodent connection with this disease, medical investigators and public health officials sought ecological information on the deer mouse and other native rodent species. Anecdotal information from residents in the afflicted areas suggested that rodents were exceptionally abundant last winter, and scientists speculated that, if true, the increased potential for rodent-human contact and disease transmission might account for the sudden epidemic. Biologists with the Sevilleta, New Mexico Long-Term Ecological Research (LTER) site have long-term data on rodent communities in the region. At the request of the CDC and the New Mexico Health Department, LTER researchers provided detailed demographic analyses from 1989-1993 for the 22 rodent species inhabiting the area. The LTER data showed tenfold population increases in various Peromyscus species and wood rats (Neotoma spp.) during the spring of 1993. Population increases occurred simultaneously in grasslands, desert-shrublands, and woodlands. Comparisons of the rodent data to the region's climatological data indicated that rodent population dynamics is associated with above-average precipitation during the winter of 1992-93, in turn leading to abundant food sources (19). 

References

  1. Marshall, E. 1993. Hantavirus outbreak yields to PCR. Science. 262:832-836. 
  2. LeDuc, J. W., J. E. Childs, and G. E. Glass. 1992. The Hantaviruses, etiologic agents of hemorrhagic fever with renal syndrome. Annu Rev Public Health. 13:79-98. 

  3. Niklasson, B. S. 1992. Hemorrhagic fever with renal syndrome, virological and epidemiological aspects. Pediatr Nephrol. 6(2):201-204. 

  4. Cosgriff, T. M. and R. M. Lewis. 1991. Mechanisms of disease in hemorrhagic fever with renal syndrome. Kidney Int Suppl. 35:S72-79. 

  5. Tkachenko E. A. and H. W. Lee. 1991. Etiology and epidemiology of hemorrhagic fever with renal syndrome. Kidney Int Suppl. 35:S54-61. 

  6. Beaty, B. J. and C. H. Calisher. 1991. Bunyaviridae--natural history. Curr Top Microbiol Immunol. 169:27-78. 

  7. Gonzalez-Scarano, F., M. J. Endres, and N. Nathanson. 1991. Bunyaviridae: Pathogenesis. Curr Top Microbiol Immunol. 169:217-249. 

  8. 1993. Emerging infectious diseases. Outbreak of acute illness. Wkly Epidemiol Rec. 68(25):186-8. 

  9. 1993. Emerging infectious diseases. Update: Hantavirus Disease. MMWR. 42(29, 31, and 42). 
  10. Sands, L. 1993. Guidelines for 

  11. diagnosis and treatment of unexplained adult respiratory distress syndrome. Arizona Department of Health Services. 
  12. Nichol, S. T., C. F. Spiropoulou, S. Morzunov, et al. 1993. Genetic identification of a Hantavirus associated with an outbreak of acute respiratory illness. Science. 262:914-917. 

  13. 1993. Hantavirus infection-Southwestern United States: interim recommendations for risk reduction. MMWR. 42(RR-11). 

  14. McKenna, P., G. VanDerGroen, G. Hoofd, et al. 1992. Eradication of hantavirus infection among laboratory rats by application of caesarian section and a foster mother techniques. J Infect. 25:181-190. 

  15. Stone, R. 1993. The mouse-pi¤on nut connection. Science. 262:833. 
  16. Kawamura, K., X. K. Zhang, J. Arikawa, et al. 1991. Susceptibility of laboratory and wild rodents to Rattus or Apodemus-type hantaviruses. Acta Virol. 35:54-63. 

  17. Hughes, J. M., C. J. Peters, M. L. Cohen, et al. 1993. Hantavirus pulmonary syndrome: an emerging infectious disease. Science. 262:850-851. 

  18. Morse, S. 1994. Personal communication. 
  19. Wong, T. W., Y. C. Chan, E. H. Yap, et al. 1988. Serological evidence of Hantavirus infection in laboratory rats and personnel. Int J Epidemiol. 17(4):887-890. 

  20. Dybas, C. 1993. NSF-funded researchers find rodent population explosion may be behind hantavirus epidemic in southwest. NSF Bulletin #93-59. 
     

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